The adult lung epithelium commonly endures injury from environmental toxins and intrinsic lung disease. Current paradigms in the lung posit that epithelial repair can be attributed to cells expressing mature lineage markers. In contrast, using lineage tracing, single cell RNA-sequencing, and orthotopic transplantation, a previously uncharacterized lineage-negative epithelial stem/progenitor (LNEPs) population was recently defined within the normal mouse lung parenchyma. Quiescent LNEPs activate a remodeling program after influenza or bleomycin injury by which they proliferate and migrate widely to occupy heavily injured areas nearly devoid of mature lineages, whereupon they differentiate appropriate to location. LNEPs appear capable of differentiating into type II cells directly or to club cells, ciliated cells, or type II cells following activation of a basal cell-like transcriptioal program. The central hypothesis of this project is that undifferentiated epithelial stem/progenitors (LNEPs) exist in mouse and human lung parenchyma, activate in response to hypoxia, and expand into the parenchyma. However, their subsequent differentiation is critically dependent on micro-environmental inputs that either support lung regeneration or promote an aberrant, failed re-organization resulting in non-functional lung, i.e. micro-honeycombing. The major objectives of the application are to define the signals that mediate LNEP activation after injury, and what determines their success or failure to regenerate normal alveolar lining cells during repair. Another key objective is to define the human equivalent of murine LNEPs and test the idea that human LNEPs activate and contribute to lung remodeling in the context of interstitial lung disease. Understanding the determinants of LNEP fate after major injury should provide new insights into lung regeneration and the pathological process by which diseased, fibrotic lungs develop.